27/09/2016 Acupunctureimprovescognitivefunction:Asystematicreview

NeuralRegenRes.2013Jun258(18):16731684. PMCID:PMC4145916
doi:10.3969/j.issn.16735374.2013.18.005

Acupunctureimprovescognitivefunction:Asystematicreview
MasonChinPangLeung,Ph.D., 1KaKeungYip, 1ChungTsungLam, 1KaShunLam, 1WaiLau, 1WingLamYu, 1
AmethystKingManLeung, 2andKwokfaiSo3
1
DepartmentofRehabilitationSciences,theHongKongPolytechnicUniversity,HungHom,HongKongSpecialAdministrativeRegion,China
2
CambridgeRegionalCollege,Cambridge,UnitedKingdom
3
DepartmentofAnatomy,andtheStateKeyLaboratoryofBrainandCognitiveScience,theUniversityofHongKong,Pokfulam,HongKong
SpecialAdministrativeRegion,ChinaGHMInstituteofCNSRegeneration,JinanUniversity,Guangzhou,GuangdongProvince,China

Correspondingauthor:MasonChinPangLeung,Associateprofessor,DepartmentofRehabilitationSciences,theHongKongPolytechnic
University,HungHom,HongKongSpecialAdministrativeRegion,China,Email:mason.leung@polyu.edu.hk(N201305064)

Authorcontributions:MasonChinPangLeung,KaKeungYip,KwokfaiSodesignedthisstudyandguidedmanuscriptwriting.ChungTsung
Lam,KaShunLam,WaiLau,WingLamYu,AmethystK.M.,Leungretrievedliterature,conductedstatisticalanalysesandwrotethemanuscript.
Allauthorsapprovedthefinalversionofthepaper.

Authorstatements:Themanuscriptisoriginal,hasnotbeensubmittedtoorisnotunderconsiderationbyanotherpublication,hasnotbeen
previouslypublishedinanylanguageoranyform,includingelectronic,andcontainsnodisclosureofconfidentialinformationorauthorship/patent
application/fundingsourcedisputations.

Received2013Apr5Accepted2013May21.

Copyright:NeuralRegenerationResearch

ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionNoncommercialShareAlike3.0Unported,which
permitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.

Abstract

BACKGROUND:
Acupuncturehasbeenusedasatreatmentforcognitiveimpairment.

OBJECTIVE:
Thisreviewassessesclinicalevidencefororagainstacupunctureasatreatmentforcognitiveimpairment.
Thisreviewalsodiscussestheproposedmechanism(s)thatcouldlinkacupuncturetoimprovedcognitive
function.

METHODS:
WesearchedtheliteratureusingPolyUonesearchfromitsinceptiontoJanuary2013,withfulltextavailable
andlanguagelimitedtoEnglish.LevelsofevidencewereexaminedusingOxfordCentreforEvidencebased
MedicineLevelsofEvidence(March,2009).

RESULTS:
Twelvestudiesmettheinclusioncriteria:3humanstudiesand9animalstudies.Levelsofevidenceranged
fromlevel1btolevel5.

CONCLUSION:
Mostanimalstudiesdemonstratedapositiveeffectofacupunctureoncognitiveimpairment.However,the
resultsofhumanstudieswereinconsistent.Furtherhighqualityhumanstudieswithgreaterstatisticalpower
areneededtodeterminetheeffectivenessofacupunctureandanoptimalprotocol.

Keywords:neuralregeneration,dementia,acupuncture,electroacupuncture,learning,cognitive,cognition,
memory,neuroregeneration
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ResearchHighlights

(1)Thisisasystematicreviewon12selectedpapersoutof227tostudyacupunctureforcognitive
impairmentinhumanandanimals.

(2)Theresultsofacupunctureprotocolsarevariable,althoughanumberofindividualstudiesreported
positiveeffectsoncognitivefunction.

(3)Furtherhighqualityresearchisneededtodeterminetheeffectivenessofacupunctureandanoptimal
protocols.

INTRODUCTION
Cognitiveimpairmentsprevailamongneurologicdisorders.Morethan60%ofpeopleexperiencedcognitive
deficitsafterstroke[1].29%ofpatientswithParkinson'sdiseasealsometthecriteriaofdementia[2].
Cognitiveimpairmentreducesthequalityoflifeofpatients,mainlybecauseitaffectsmoodandmemory.
Functionallimitationduetocognitiveimpairmentcanalsodecreasequalityoflife.Studysuggeststhatpoor
cognitivefunctioningisassociatedwithreducedfunctionalindependence,socialparticipation,depressive
mood,andlifesatisfaction1yearpoststroke[3].AccordingtotheWorldHealthOrganization,thenumberof
peoplewithdementiawillcontinuetogrow.Thetotalpopulationwithdementiaworldwidein2010was
estimatedtobe35.6millionandwasprojectedtonearlydoubleevery20years[4].Thetotalestimated
worldwidecostsofdementiawereUS$604billionin2010[4].Itdoescreateaseriousfinancialburdenonthe
society.Sincetreatmentforcognitiveimpairmenthasnotbeenwelldeveloped,someclinicianshave
suggestedthatacupuncturecouldbeanalternativetreatmentofcognitiveimpairment.

AcupunctureisanalternativemedicinemethodologythatoriginatedinancientChina.Itisanimportantpart
ofChinesemedicinethatinvolvestheinsertionoffine,solidneedlesintoacupuncturepointsintheskin.
AccordingtotraditionalChinesemedicine,stimulatingthesepointscouldcorrectimbalancesoftheflowof
Qithroughmeridians[5].

Therearemanydifferentwaystopracticeacupuncture.Inthisreview,wewillfocusontraditional
acupuncturewhereneedleswereinsertedintothebodyaccordingtotraditionalChinesemedicine
framework[6]andelectroacupunctureinvolvedpassingapulsedcurrentthroughthebodytissuesvia
acupunctureneedles.

AcupuncturehasbecomemorepopularnotonlyinChinabutalsoinotherforeigncountries.Acupuncture
hasbeenclaimedtobeeffectiveforawiderangeofconditions,suchaspain,musculoskeletaldisordersand
severalneurologicdiseases[7].However,itsuseforcognitivediseaseshasbeenmuchlessemphasized.

Inordertojustifytheefficacyandmakerecommendationsregardingacupuncturetreatmentforcognitive
impairment,weconductedareviewthatsummarizestheevidencefrompreviousstudiesonthistopic.

DATAANDMETHODS

Searchstrategy
Thefollowingelectronicdatabasesweresearched:PolyUonesearchincludedSciVerseScienceDirect
(Elsevier),MEDLINE(NLM),OneFile(GALE),HealthReferenceCenterAcademic(Gale),SpringerLink,
AmericanPsychologicalAssociation(APA),PMC(PubMedCentral),OxfordJournals(OxfordUniversity
Press),HindawiJournals,SagePublications(CrossRef),BenthamScience(IngentaConnect),PLoSandthe
followingkeywordswereused:acupuncture,cognition,cognitive,dementia,Alzheimer'sdisease,memory.

Inclusioncriteria
Twoindependentreviewerswereresponsiblefordataretrievalandqualityevaluation.

Typesofpublication:Allrandomizedcontrolledtrials,randomizedcrossovertrialsandcontrolledtrialsthat
measuredatleast1cognitivedomain.OnlyEnglisharticleswereincluded.Nopublicationdatelimitswere

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set,andthesearchwascompletedinJanuary2013.

Participants:Humanoranimalstudiesoncognitiveimpairmentwereincluded.

Interventions:Weincludedtrialsinwhichtherewasacomparisonbetweenatreatmentgroupthatreceived
acupuncturewith/withoutcombinedtreatment,andacontrolorcomparisongroupthatreceivedeitheran
alternativeformofinterventionornotreatment.

Outcomes:Theoutcomemeasureofinterestwascognitivefunction.Thisincludedanyneuropsychological
testdesignedtodetectachangeincognitivefunctioninanydomainforexample,memory,learningorthe
MiniMentalStateExamination.

Publishedarticlesthatdidnotmeettheinclusioncriteriawereexcludedusingtitles,abstractsandfulltextas
appropriate.

RESULTS

Identificationandselectionofstudies
Atotalof227articleswereidentifiedfromsearchesperformedinJanuary2013.Eightytwoarticleswere
duplicatedand96wereexcludedduetoirrelevancetoacupunctureand/orcognition,leaving49articlesfor
furtherevaluation.Thirtythreeofthemwerenotexperimentaltrials.Fourremainingstudiesdidnotmeetthe
inclusioncriteria,becausetheydidnothavecognitiveoutcomemeasurements.Intheend,12studieswere
includedinthisreview.Threestudieswerehumantrials,whileotherninestudiesusedanimals(Figure1).

Descriptionofstudies

Levelofevidence

StudieswereclassifiedbyOxfordCentreforEvidencebasedMedicineLevelsofEvidence(March2009)
[8].Amonghumantrials,RorsmanandJohansson[9]wasclassifiedaslevel1bevidence,Chouand
colleagues[10]aslevel2bevidenceandChenetal[11]aslevel4evidence.Alltheanimalstudiesselected
wereclassifiedaslevel5[12,13,14,15,16,17,18,19,20](Table1).

Participants

Atotalof105subjectsreceivedacupuncturetreatmentacrossthe3studiesusinghumanassubjects[9,10,11].
Afurther116subjectsactedascontrolorreceivedothertreatmentbesidesacupuncture.Onehundredand
sixtysevensubjectswerebetween59and90yearsoldandwithMiniMentalStateExaminationscoresless
than24[9,10].Therewere87subjectswithstroke,33subjectswithstrokeonsetfrom13to33months[9]
and54subjectsweretreated5to10daysafterstroke[11].Atotalof134vasculardementiasubjectswith
illnesscourserangingfrom1to7yearswerealsoincluded[10](Table2).

Atotalof421rats(ratswhichdiedorscreenedoutinanycognitiveimpairmentcheckaftersurgerieswere
excluded)wereusedinstudies[12,13,14,15,16,17,18,19,20].Inordertopreparecognitiveimpairedsubjects,
150ratshadbeeninjectedaclotintotheinternalcarotidartery[12,13,16,18].Fortyfivesenescence
acceleratedpronemouseratswereused[14].Twentyratswereisolated[15].Sixteenratswereunderchronic
mildstress[17].Theoriginofthecerebralarteriesof15ratswereocculted[19]or28wereinducedwith
cognitiveimpairmentbychronicinjectionofcorticosterone[20].Atotalof117ratshadacupuncture
treatment,whereas304ratsactedascontrolorreceivedothertreatments.

Threeclinicalandnineanimalstudiesexaminedtheeffectofacupunctureonhumanandrats,respectively.
Noadverseeffectswerereportedaftertreatment.

Intervention

Acupuncturestimulationwasappliedusingavarietyofacupoints,needlestimulationandfrequencysetting.
SelectedacupointsincludedLI4,LI11,GV20,ST36,ST40,GB34,EX36:1,EX28:2,(1study)[9],PC6,
HT7(1study)[10],GV20,GV16,GB20,EXHN5,LI4,LR3,EXHN1,EXHN3(1study)[11],
Yiqitiaoxue,fubenpeiyuanacupuncturemethodCV17,CV12,CV6,ST36,SP10(5studies)

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[12,13,14,16,18],ST36(1study)[15],PC6vs.TE5(1study)[17],GV20(1study)[19],HT7vs.TE5(1
study)[20].Needlestimulationwaseithermadebymanualtwistingorelectricalstimulation.Control
interventionconsistedofneedleinsertiontoanonacupoint.Treatmentdurationrangedfrom30to180
secondsforeachacupoint(manualtwisting)[12,17]20to30minutesforeachacupoint(electrical
stimulation)[10,15],rangedfrom2sessionsaweekto6sessionsaweek[10,12].Thetotalsessionnumber
rangedfrom4to36[11,15].

Outcomemeasurements

Inthehumanstudies,cognitivefunctionwhichwastheprimaryoutcomewasmeasuredbyLoewenstein
OccupationalTherapyCognitiveAssessment,forgeriatricpopulation[10],MiniMentalState
Examination[9,11]andBlessBehavioralability[11]wereused.Othercognitivefunctionalaspectswere
measured,includingverballearningandmemorybyReyAuditoryVerbalLearningTest,visualmemoryby
FacialRecognitionMemory,visualattentionbyStarCancellationTest,visualperceptionbyTime
Perception,receptivelanguagebyTokentestandwordfluencybyFastApplicationSwitching[9].Secondary
outcomewasqualityoflife,whichwasassessedbySF36questionnaireandStrokeSpecificQualityofLife
Scale[11].

Fortheanimalstudies,thelearningabilityandmemoryaspectsofcognitivefunctionwereassessedusing
MorrisWaterMazetest,whichincludedhiddenplatformtrial[12,13,14,16,18,19,20],probe
trial[12,13,14,16,20]andreversaltrial[12,13,14,16]andvisibleplatformtrial[12,13,14,16,20],andpassive
avoidancetask[15,17](Tables3and4).

Enzymeactivitiesofsuperoxidedismutase[13,19],catalase[13,19],glutathioneperoxidase[13,19],nerve
growthfactor[15],brainderivedneurotrophicfactor[15],acetylcholinesterase[17,20],hexokinase[18],
pyruvatekinase[18],glucose6phosphatedehydrogenase[18],cholineacetyltransferase[20]andexpression
ofcopperzincsuperoxidedismutasemRNAanditsprotein[13],Bcl2protein[16],Baxprotein[16],lipid
peroxidationproduct,malondialdehyde[19]inbrain,braincellproliferation[14]andnervecellapoptosis[16]
weremeasuredforinvestigatingthemechanismsbywhichacupunctureimprovedcognitivefunction.

DISCUSSION

Effectofacupunctureoncognitionofhumansubjects
ElectroacupuncturecouldimproveLoewensteinOccupationalTherapyCognitiveAssessment,forgeriatric
population:orientation,perception,praxis,andattentioninpatientswithstroke.

Also,ChinesemedicineplusrehabilitationandacupuncturecouldimprovevasculardementiapatientsBless
Behavioralability(Blessbehaviorscore)andMiniMentalStateExamination[9,10].

Effectofacupunctureoncognitivefunctionfordementiarats
Ninestudies[12,13,14,15,16,17,18,19,20]examinedtheeffectofacupunctureoncognitivedeficitinduced
bysurgicalemboliinjection,socialisolation,geneticpreexposure,chronicmildstressandchronicinjection
ofcorticosteroneofratsseparately.Acupuncturewasshowntohaveasignificantbeneficialeffecton
cognitivefunction,includinglearningorrelearningabilityandmemoryinallanimal
studies[12,13,14,15,16,17,18,19,20].TheyweremeasuredbyMorrisWaterMazetestincludingalltypesof
trialmentionedbefore[12,13,15,17,18,19,20]andpassiveavoidancetask[14,16].

However,duetosomelimitationsmentionedinthesestudies,thiseffectmightbesubjectedtosomebiases.

Generallimitationsofliteratureincluded

Humanstudies

Therewereonlythreehumanstudiesincludedinthisreviewoutof12published[9,10,11].Amongthethree
selectedstudies,twostudieshadasmallsamplesize,lessthan20subjectspergroup[9,10].Noneofthem
hadjustifiedthechoiceofsamplesize.Threestudieswererandomized,butmethodsofrandomizationwere
notstated.Onestudydidnotblindthetester[11].Theresultsmightbesubjectedtobiasoftester.Three

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studiesonlyinvestigatedthecombinedeffectofacupuncturewithconventionalrehabilitationorChinese
medicine,noexactcontrolgroupreceivednotreatmentandnotreatmentgroupreceivedacupuncture
alone[9,10,11].Twostudiesdidnothavefollowupassessment[10,11].Thelonglastingeffectof
acupuncturecouldnotbejustified.

Ratstudies

Therewerenineratstudiesselectedforourreview[12,13,14,15,16,17,18,19,20].Evenwhenthestudies
werewelldesigned,animalstudieswereconsideredatlevelfiveofevidencewhichisthelowest.Infact,
thereweresomelimitationsintheseanimalstudies[12,13,14,15,16,17,18,19,20].Sixstudieshad1015rats
ineachgroup[12,13,14,15,16,18].Threestudieshad510ratsineachgroup[17,19,20].Noneofthemhad
justifiedthechoiceofsamplesize.

Sixstudiesstatedtheyhadallocatedtheratsrandomly,butnoneofthemstatedthemethodof
randomization[12,13,14,16,18,20].Sevenstudiesdidnotblindthetester[12,13,15,16,17,18,19].Theresults
mightbesubjectedtobiasoftester.Allstudieshadanimpairedtreatmentgroupreceivingonlyacupuncture,
andanimpairedcontrolgroupreceivingnoorshamtreatment[12,13,14,15,16,17,18,19,20].Itwasgoodto
demonstratetheeffectofacupuncture.Eightstudiesincludedanormalcontrol
group[12,13,14,15,16,17,18,20].Itwasusefultoexhibitthemagnitudeofrecoveryduetoacupuncture
treatmenteffect.Fivestudiesdidnotconductascreeningtrialtoconfirmthattherewerecognitive
impairmentsintherats[14,15,17,19,20].

Theresultsmightbeaffectedbyinclusionofsomeoftheratswhichdidnotsufferfromcognitiveimpairment
aftersurgeryorotherprocedures.Fourstudiesdidnotconductavisibleplatformtrialoropenfieldtestto
excludetheeffectofmotordeficitormotivationproblemasaresultofMorrisWaterMazeorpassive
avoidancetest[12,14,16,20].

Therewasnofollowupinanyoftheratstudies[12,13,14,15,16,17,18,19,20]henceitwasnotpossibleto
evaluatethelonglastingeffectofacupuncture.

Sincethetreatmentprotocolsandcausesofcognitiveimpairmentvaried,itremainsdifficulttosuggestan
optimalprotocolandindication.

Mechanismofacupunctureeffectofcognitiveimpairment

Acetylcholinesteraseandcholineacetyltransferase

PreviousstudieshadshownthatthemostprofoundchangeinpatientswithAlzheimer'sdiseasewasa
progressivereductionintheactivityofacetylcholinesteraseintheneocortexandhippocampuscompared
withnormalsubjects[21,22].Also,cholineacetyltransferaseactivitywashighlycorrelatedwiththeseverity
ofdementiaacrosstheneocortexoftheAlzheimer'sdiseasecases[21].Therefore,itwasgenerallyaccepted
thatthecellularlossanddysfunctionofcholinergicneuronsresultindevelopmentofdementiainAlzheimer's
disease[23].

Inthisreview,twostudiesinvestigatedtheeffectofacupunctureonacetylcholinesteraseactivityinthe
hippocampus.Onestudyfoundthattheacetylcholinesterasereactivityinthehippocampusofachronicmild
stressgroupofratswassignificantlylowerthanthatofthecontrols(P<0.0001),andacupunctureatPC6
couldincreasetheacetylcholinesterasereactivityinbothhippocampalCA1(P<0.05)andCA3(P<0.05)
inchronicmildstressgroup.Learningandmemoryabilityoftheratsweretestedbypassiveavoidancetask,
andthePC6acupuncturegroupshowedimprovementinlearningandmemorycomparedtothechronicmild
stressgroup(P<0.001)[17].Anotherstudyfoundthatacetylcholinesterasereactivityinthehippocampal
CA1duetochronicexposuretoexogenouscorticosteronewassignificantlyrestoredbyacupunctureatHT7
(P<0.05),buttherestorationintheCA3areawasnotstatisticallysignificant(P=0.526).Inthestudythat
usedMorrisWaterMazetesttomeasurethelearningandmemoryfunctions,theHT7acupuncturegrouphad
significantlyreducedescapelatency(P<0.01onday5andP<0.05onday6)andspentmoretimearound
theplatformareainprobetrialcomparedwithimpairedgroup(P<0.05)[20].

Theabovestudyalsoinvestigatedtheeffectofacupunctureoncholineacetyltransferaseactivityinbrain.The
numberofcholineacetyltransferaseimmunoreactiveneuronswassignificantlyincreasedinthemedial

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septumregionandthehippocampalCA1intheHT7acupuncturegroup(P<0.05),comparedwiththe
impairedgroup[20].Nevertheless,therelationshipbetweenenzymeactivitiesandlearningandmemory
functionswasnotinvestigatedinthesetwostudies.

Thismightsuggestthatacupunctureattenuatedtheimpairmentsofmemoryandcognitionbyrestoring
cholinergicneurochemicalabnormalities.However,bothstudieshadonlyafewratsineachgroup(Kimet
al[17]:56ratsineachgroupLeeetal[20]:4ratsineachgroupwereusedforacetylcholinesteraseand
cholineacetyltransferasetests).InthestudyconductedbyLeeetal[20],therewasnoscreeningforcognitive
impairmentaftercorticosteroneinjection.Withalltheselimitations,futurestudiesareneededtoexaminethe
thoroughrelationshipbetweenacupunctureandcholinergicneurochemicalactivitiesindifferentareasofthe
brain.

Morewelldesignedstudiesarerequiredtoestablishthemechanismofacupunctureeffectoncognitive
functionwithrespecttoactivitiesofcholinergicneuronsinthebrain.

Effectonsuperoxidedismutase,catalase,glutathioneperoxidase

Freeradicalsandtheoxidativestressweretheprimecandidatestoberesponsibleforproducingtheneuronal
damagesandcognitivedeficits[24].Comparingpatientswithvasculardementia,withAlzheimer'sdisease
andcontrolgroup,antioxidantdefensedecreasedandthesusceptibilitytooxidativestressincreased[25].

Thereweretwostudiesfromthisreviewwhichinvestigatedtheeffectsofantioxidantslikesuperoxide
dismutase,catalase,glutathioneperoxidaseinrelationtoimprovementincognition[13,19].

Bothacupunctureandgingerpharmacopunctureinwhichgingerextractwasinjectedintoacupointinduced
significantelevationofcatalaseandglutathioneperoxidaseactivitiesinthecerebralcortexandhippocampus
comparedwiththeshamgroup(P<0.05forall).However,bothacupunctureandgingerpharmacopuncture
producedasignificantelevationofsuperoxidedismutaseactivityonlyinthehippocampuscomparedwith
sham(P<0.05)[19].

Anotherstudyalsoshowedthattherewasasignificantdecreaseinthesuperoxidedismutaseactivityin
hippocampusofratsinimpairedandplaceboacupuncturegroupswhencomparedwiththenormalrats(P<
0.05).However,acupuncturaltreatmentcausedasignificantincreaseinhippocampalsuperoxidedismutase
activity.Asignificantreductionintheglutathioneperoxidaseactivitywasfoundinthehippocampusofratsin
theimpairedandplaceboacupuncturegroupswhencomparedwiththenormalrats(P<0.01).After
acupuncturaltreatment,asignificantincreaseofglutathioneperoxidaseactivitywasobservedinthe
hippocampus.However,thecatalaseactivityhadnosignificantdifferenceamongallthefivegroups(P>
0.05)[13].

Theinsignificantchangesinthecatalaseactivityinthesecondstudymightbeduetothefactthatthecatalase
activityintheratbrainwasverylow[13,26].Acupuncturaltreatmentincreasedsuperoxidedismutaseand
glutathioneperoxidaseactivitiesinthehippocampusofthecerebralmultiinfarctionrats.Theincreaseof
superoxidedismutaseinducedbyacupuncturecouldconvertsuperoxideradicalsintohydrogenperoxide.
Subsequently,theincreaseofglutathioneperoxidaseandcatalaseinducedbyacupuncturebrokedown
hydrogenperoxidetowatermolecules,preventedhydrogenperoxidefromconvertingintohydroxylradicals,
themosttoxicformoffreeradicalswhichareinvolvedinanumberofbrainlesionsandinbrain
aging[13,26].

However,therewerestillsomeconfoundingfactors.Toillustratethis,onlyasmallnumberofratswere
sacrificedtoexaminetheirbrains(24rats[13]and15rats[19]respectively).InJittiwat'sstudy,therewasno
normalcontrolgroup[19].Thereforetherewasnocomparisonofcatalaseandglutathioneperoxidaseactivity
betweencognitiveimpairedsubjectsundergoingacupunctureandnormalsubjects,butonlycomparisonwith
cognitiveimpairedsubjectswithshamacupuncture.

EffectofcopperzincsuperoxidedismutasemRNAanditsprotein

Inthisreview,onestudy[13]investigatedtheeffectofacupunctureoncopperzincsuperoxidedismutase
mRNAanditsprotein.ThedecreasedexpressionofcopperzincsuperoxidedismutasemRNAinthe
hippocampuswasobservedintheimpairedratsandtheexpressionofcopperzincsuperoxidedismutase
mRNAinthehippocampussignificantlyincreasedintheacupuncturetreatedgroup(P<0.01).Copperzinc
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superoxidedismutasepositivecellsinthehippocampusofthenormalgroupwashigherthaninsham
operatedgroups,butwasnotstatisticallysignificant(P>0.05).Thecopperzincsuperoxidedismutase
positivecellsintheacupuncturegroupweresignificantlyhigherthanthatintheimpairedgroup(P<0.01).
Thevalueoftheplaceboacupuncturegroupdidnotdifferfromtheimpairedgroup.Theexpressionpattern
ofcopperzincsuperoxidedismutaseproteinwassimilartothatofitsmRNA.Therewasnodifferenceofthe
copperzincsuperoxidedismutasepositivecellsbetweennormalandshamoperatedgroups(P>0.05).The
copperzincsuperoxidedismutaseintheacupuncturegroupwassignificantlyhigherthanthatintheimpaired
group(P<0.01).Thevaluefortheplaceboacupuncturegroupdidnotdifferfromtheimpairedgroup.

Thisstudyalsoshowedthatthelowercopperzincsuperoxidedismutaseexpressionofthecerebralmulti
infarctionratsincreasedintheacupuncturegroup.Theseresultssuggestthatacupuncturaltreatmentcould
maintaintheoxidantantioxidantbalancetoagreaterextent[13].

Toconclude,acupuncturecouldincreasethecopperzincsuperoxidedismutaseexpression,consequently
exertingantioxidanteffectsandimprovecognition.However,acupuncturemightimprovecognitivedeficits
bymanypossibleways,andtheresultmightbeaffectedbysomeconfoundingfactors,includingsmall
samplesize.Furtherstudiesarerequiredtoelucidatethemechanismsindetail.

Effectofneurotrophinregulation

Neurotrophins,aclassofgrowthfactors,areafamilyofproteinsthatinducethesurvival,development,and
functionofneurons.

Inourreview,twooftheneurotrophins,i.e.brainderivedneurotrophicfactorandnervegrowthfactor,were
investigatedinrats[15,20].Brainderivedneurotrophicfactorplayedanimportantroleinhippocampallong
term[27].Nervegrowthfactorwasrequiredforthesurvivalofdevelopingsympatheticandsensory
neurons[28].

Brainderivedneurotrophicfactorandnervegrowthfactor:Mannietal[15]studiedtheeffectofelectro
acupunctureinsocialisolatedmiceonbrainderivedneurotrophicfactorandnervegrowthfactor
concentrationinhypothalamus,hippocampusandstriatum.

Onlytheisolatedelectroacupuncturegroupshowedasignificantdecreaseofbrainderivedneurotrophic
factorinthehippocampuscomparedtoisolatedcontrolgroup(P<0.05).Whileothergroupsshowedno
significantdifference[15].

Fornervegrowthfactor,nodifferencesbetweenallfourgroupswerefoundinthehypothalamus.Inthe
striatumandhippocampus,theisolatedelectroacupuncturegroupshowedthelowestvalueswhencompared
toisolatedcontrolandnonisolatedelectroacupuncturegroups(P<0.05)[15].

Thelearningabilitiesweremeasuredbypassiveavoidancetask.Inacquisitionphase,isolatedcontrolgroup
hadlowerlatencytostepthroughduring10trialscomparedtoisolatedelectroacupunctureandnonisolated
controls(P<0.01).Alsoisolatedcontrolshadhighvaluesofthenumberoftrialstoreachlearningcriteria
comparedtotheotherthreegroups(P<0.05).Thissuggestedadelayinlearningperformancesofthe
isolatedcontrolgroups[15].

ThisstudysuggestedthatelectroacupunctureonST36couldhelpsociallyisolatedmicetoimprovethedelay
oflearningperformancesandelectroacupuncturehadadownregulationeffectonbrainderivedneurotrophic
factorandnervegrowthfactor.However,thetreatmentcourseforelectroacupuncturelastedonly4days,and
itfailedtoshowanydifferencesintheretentionphaseofpassiveavoidancetask[15].

Brainderivedneurotrophicfactor:Leeetal[20]studiedtheeffectofacupunctureoncorticosteroneinduced
cognitiveimpairmentratsonbrainderivedneurotrophicfactormRNAexpressioninthehippocampus.

Inthehippocampus,brainderivedneurotrophicfactormRNAexpressionincorticosterone(impaired)group
significantlydecreasedcomparedtothatinthenormalgroup(P<0.001).Thebrainderivedneurotrophic
factormRNAexpressionincorticosteroneHTgroupsignificantlyincreasedcomparedtocorticosterone
group(P<0.05),andthebrainderivedneurotrophicfactormRNAlevelwassimilartothatofnormalratsin
thenormalgroup(P<0.001)[20].

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ThelearningabilitiesweremeasuredusingMorrisWaterMazethecorticosteroneHTgroupwas
significantlyshorterinescapelatencyandlongerretentiontimecomparedwiththecorticosteronegroup
(bothP<0.05).ItshowedtherecoveryofspatialmemoryinthecorticosteroneHTgroup[20].

ThisstudysuggestedthatacupunctureonHT7couldhelptoimprovecognitiveimpairmentduetochronic
corticosteroneinjectionandhadanupregulatingeffectonbrainderivedneurotrophicfactorexpression.
However,only3ratsineachgroupweresacrificedforbrainderivedneurotrophicfactoranalysis[20].

Thesetwostudiessuggestedthatbrainderivedneurotrophicfactorwasaffectedindifferentcasesof
cognitiveimpairment.Applyingacupuncturetodifferentacupointscouldhelptonormalizethebrainderived
neurotrophicfactorlevelbyeitherupordownregulation[15,20].

Bcl2,Baxandapoptosis

Themembersofthebcl2familyofgenesplayanimportantroleinregulatingapoptosis[29].Onememberof
thefamily,Bcl2,functionsasarepressorofapoptosiswhereasanothermemberofthefamily,Bax,actsasa
promoterofcelldeath[30].

Onestudyinourreviewstudiedtheeffectofacupunctureonmemoryperformance,theexpressionofBcl2
family,andapoptosisinhippocampalCA1regionaftercerebralmultiinfarctioninrats[16].Theacupuncture
groupshowedimprovementsinacquisition(P<0.05),relearningability(P<0.05)andretentionofspatial
memory(P<0.05)whencomparedtotheimpairedandplaceboacupuncturegroups.ThemRNA
expression(P<0.01)andproteinexpressionofBcl2(P<0.01)wasupregulatedintheacupuncturegroup
whencomparedwiththeimpairedgroupontheotherhand,themRNAexpression(P<0.01)andprotein
expressionofBax(P<0.01)decreasedintheacupuncturegroupwhencomparedwiththeimpairedgroup.
Forapoptosis,thenumberofapoptoticcellssignificantlydecreased(P<0.05)intheacupuncturegroup
whencomparedwiththeimpairedgroup.

Accordingtotheseobservations,acupuncturemightprotecttheneuronsinthehippocampusbyregulating
theapoptoticcelldeath,thuspromotingcellsurvivalandimprovecognitiveperformances.Inorderto
constructacompletemechanism,furtherwelldesignedstudiesshouldbeconductedtoinvestigatetheeffect
ofacupunctureonapoptosisindifferentareasofthebrainaftermultiinfarction.

Acupunctureeffectsonbraincellproliferationandnervecellapoptosis

Previousstudieshaveshownthatrat'sbraincellproliferationcouldbeinfluencedbyexercise[31,32].Inour
review,onegroupstudiedtheeffectofacupunctureoncognitivefunctionandbraincellproliferationin
senescenceacceleratedpronemouseratswhichweregeneticpreexposuretoAlzheimerdiseaselikedisease
rats[14].Therewassignificantdecreaseofcellproliferationinthedentategyrus,lateralventricles,corpus
callosumanddorsumofalveushippocampiinthesenescenceacceleratedpronemousecontrolgroupwhen
comparedtonormalcontrolgroup(P<0.05),whilesignificantincreasewasnotedinsenescenceaccelerated
pronemouseacupuncturegroupwhencomparedtocontrolgroupandsenescenceacceleratedpronemouse
nonacupointcontrolgroups(P<0.01).Therewaslearningdeficit(hiddenplatformtrial),memorydeficit
(probetrial)andimpairedrelearningability(reversaltrial)ofcontrolgroupwhencomparedtonormalcontrol
group(P<0.01).Therewasincreaseoflearningandmemoryabilityinacupuncturegroupcomparedto
controlgroup(P<0.05)andnonacupointcontrolgroups(P<0.01),andalsoincreaseofrelearningability
inacupuncturegroupcomparedtocontrolgroupandnonacupointcontrolgroups(P<0.01)[14].

Theseresultssuggestthatacupuncturecouldimprovecognitivefunctioninsenescenceacceleratedprone
mouserats.Thisimprovementmightbeduetotheincreaseofcellproliferationinmultiregionsofthebrain.
Futurestudiesshouldinvestigatetherelationshipbetweenbraincellproliferationandcognitivefunction.
ResearcherscouldprogresstotesttheeffectsonhumansubjectswithAlzheimer'sdiseaseinordertoprovide
higherlevelofevidencetosupporttheuseofacupunctureasanalternativetreatmentindementia
rehabilitation.

Effectofglycometabolicenzymesregulation

Somestudieshaveindicatedthattherewasabnormalenergymetabolisminvasculardementiapatient
brain[33,34].Recentstudiesshowedthatacupuncturecouldincreasecerebralglucosemetabolisminhuman

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withvasculardementia[35],andsuggestedthatcognitiveimpairmentcausedbyvasculardementiamightbe
relatedtoimpairedglucosemetabolisminthebrain.

Inourreview,onestudyinvestigatedtheeffectsofacupunctureontherightcortexandhippocampusinrat
brainglycometabolicenzymes,i.e.,hexokinase,glucose6phosphatedehydrogenaseandpyruvatekinase,in
multiinfarctdementiarats.Impairedratsandimpairedratswithnonacupuncturehadsignificantlower
enzymeactivitiesthannormalrats(normalgroup)(P<0.01).Impairedratswithacupuncturehadsignificant
higherenzymeactivitiesthanimpairedratsandimpairedratswithnonacupuncture(P<0.01),andthe
valueswereincreasedtowardnormalgroup.ThelearningabilitiesweremeasuredbyMorrisWaterMaze.
Impairedratsandimpairedratswithnonacupuncturehadsignificanthigherescapelatencythannormal
group(P<0.01)andimpairedratswithacupuncturehadsignificantlowerescapelatencythanimpairedrats
andimpairedratswithnonacupuncture(P<0.01),andtherewerenodifferenceswhencomparedtonormal
group(noPvalueprovided).ButtherelationshipbetweenenzymeactivitiesandescapelatencyinMorris
WaterMazewasnotinvestigated[18].

Theseresultssuggestthattheimprovementinlearningabilities,oneaspectofcognitivefunction,was
associatedwiththeupregulationofglycometabolicenzymeactivities.However,asonlyhiddenplatform
trialwasusedinMorrisWaterMaze,thedecreaseofescapelatencyinimpairedratswithacupuncture
comparedtoimpairedratsmightbeduetotheotherconfoundingfactors,includingimprovementoflocal
motionabilityandmoodupregulation.Futurestudiesshouldinvestigatetherelationshipbetweenthose
enzymeactivities,ATPconcentrationorconsumptioninthebrainandcognitivefunction,andstudythe
thoroughmechanismofacupunctureeffectsoncognitivefunctionwithrespecttoglycometabolicenzyme
activitiesinthebrain.

Implicationsforfutureresearch
Whileacupuncturehasbeenadvocatedasatreatmenttoimprovecognitivefunctionimpairmentinpatients
withdementia,alackofhighqualityresearchinthisareahassofarpreventedthedevelopmentofsound
recommendationsforclinicalpractice.Morehighqualityresearchonhumanisessential.Itmightnotbe
ethicaltohaveacontrolgroupwithoutanytreatment.Futureresearchshouldfocusontheeffectof
acupunctureversusconventionrehabilitation,medicines,andtheeffectofcombinedtreatments,tofindout
themostcosteffectivetreatmentthatpromotesthegreatestmagnitudeofrecovery.Also,afollowup
assessmentshouldbeincludedtoinvestigatethelonglastingeffectofacupuncture.Moreover,theacupoints
andprotocolsthatwereusedinpublishedresearchvariedalot.Therefore,standardizedtreatmentprotocols
areneededandshouldbedeveloped.

Acupuncturehasbeenusedtotreatcognitiveimpairment,butthereisalackofhighqualityevidencein
humans.Sincetherewereonlyalimitednumberofpublishedhumanstudiesandtheresultsofthethree
humanstudiesincludedinourreviewwerenotconsistent,thismaybeduetomanyconfoundingfactors.
Therefore,wecannotdrawanyconclusionontheeffectivenessofacupunctureforcognitivefunction
improvementinhumans.Theresultsofacupunctureprotocolsarevariable,althoughanumberofindividual
studiesreportedpositiveeffectsoncognitivefunction.Furtherhighqualityresearchisneededtodetermine
theeffectivenessofacupunctureandanoptimalprotocol.

Footnotes
Conflictsofinterest:Nonedeclared.

(ReviewedbyXuXM)

(EditedbyLiuWJ,LiCH,SongLP)

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FiguresandTables

Figure1

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Flowchartoftheliteratureselectionprocess.

Table1

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Studydesign

Table2

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Majorfindingsofhumanstudies

Table3

Majorfindingsofratsstudies(MorrisWaterMazeTest)

Table4

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Majorfindingsofratsstudies(passiveavoidance)

ArticlesfromNeuralRegenerationResearchareprovidedherecourtesyofMedknowPublications

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